This invention relates to transdermal molecular transportation. More specifically, this invention relates to methods and apparatus for producing homogenous cavitation in a transdermal transport system.
Drugs are routinely administered either orally or by injection. The effectiveness of most drugs relies on achieving a certain concentration in the bloodstream. Although some drugs have inherent side effects which cannot be eliminated in any dosage form, many drugs exhibit undesirable behaviors that are specifically related to a particular route of administration. For example, drugs may be degraded in the GI tract by the low gastric pH, local enzymes or interaction with food or drink within the stomach. The drug or disease itself may forestall or compromise drug absorption because of vomiting or diarrhea. If a drug entity survives its trip through the GI tract, it may face rapid metabolism to pharmacologically inactive forms by the liver, the first-pass effect. Sometimes the drug itself has inherent undesirable attributes such as a short half-life, high potency or a narrow therapeutic blood level range.
Recently, efforts aimed at eliminating some of the problems of traditional dosage forms involve transdermal delivery of the drugs (TDD). Topical application has been used for a very long time, mostly in the treatment of localized skin diseases. Local treatment, however, only require that the drug permeate the outer layers of the skin to treat the diseased state, with little or no systemic accumulation. Transdermal delivery systems are designed for, inter alia, obtaining systemic blood levels, and topical drug application. For purposes of this application, the word xe2x80x9ctransdermalxe2x80x9d is used as a generic term to describe the passage of substances to and through the skin.
TDD offers several advantages over traditional delivery methods including injections and oral delivery. When compared to oral delivery, TDD avoids gastrointestinal drug metabolism, reduces first-pass effects, and provides sustained release of drugs for up to seven days, as reported by Elias in Percutaneous Absorption: Mechanisms-Methodology-Drug Delivery, Bronaugh, R. L. Maibach, H. I. (Ed), pp 1-12, Marcel Dekker, New York, 1989.
The transport of drugs through the skin is complex since many factors influence their permeation. These include the skin structure and its properties, the penetrating molecule and its physical-chemical relationship to the skin and the delivery matrix, and the combination of the skin, the penetrant, and the delivery system as a whole. Particularly, the skin is a complex structure. There are at least four distinct layers of tissue: the nonviable epidermis (stratum corneum, SC) the viable epidermis, the viable dermis, the subcutaneous connective tissue. Located within these layers are the skin""s circulatory system, the arterial plexus, and appendages, including hair follicles, sebaceous glands, and sweat glands. The circulatory system lies in the dermis and tissues below the dermis. The capillaries do not actually enter the epidermal tissue but come within 150 to 200 microns of the outer surface of the skin.
In comparison to injections, TDD can reduce or eliminate the associated pain and the possibility of infection. Theoretically, the transdermal route of drug administration could be advantageous in the delivery of many therapeutic drugs, including proteins, because many drugs, including proteins, are susceptible to gastrointestinal degradation and exhibit poor gastrointestinal uptake, proteins such as interferon are cleared rapidly from the blood and need to be delivered at a sustained rate in order to maintain their blood concentration at a high value, and transdermal devices are easier to use than injections.
In spite of these advantages, very few drugs and no proteins or peptides are currently administered transdermally for clinical applications because of the low skin permeability to drugs. This low permeability is attributed to the SC, the outermost skin layer which consists of flat, dead cells filled with keratin fibers (keratinocytes) surrounded by lipid bilayers. The highly-ordered structure of the lipid bilayers confers an impermeable character to the SC (Flynn, G. L., in Percutaneous Absorption: Mechanisms-Methodology-Drug Delivery.; Bronaugh, R. L., Maibach, H. I. (Ed), pages 27-53, Marcel Dekker, New York 1989). Several methods have been proposed to enhance transdermal drug transport, including the use of chemical enhancers, i.e. the use of chemicals to either modify the skin structure or to increase the drug concentration in a transdermal patch (Burnette, R. R., in Developmental Issues and Research Initiatives; Hadgraft J., Guy, R. H., Eds., Marcel Dekker: 1989; pp. 247-288; Junginger, et al. in Drug Permeation Enhancement; Hsieh, D. S., Eds., pp. 59-90; Marcel Dekker, Inc. New York 1994) and the use of applications of electric fields to create transient transport pathways [electroporation] or to increase the mobility of charged drugs through the skin (iontophoresis) (Prausnitz Proc. Natl. Acad. Sci. USA 90, 10504-10508 (1993); Walters, K. A., in Transdermal Drug Delivery: Developmental Issues and Research Initiatives, Ed. Hadgraft J., Guy, R. H., Marcel Dekker, 1989). Another approach that has been explored is the application of ultrasound.
Ultrasound has been shown to enhance transdermal transport of low-molecular weight drugs (molecular weight less than 500) across human skin, a phenomenon referred to as sonophoresis (Levy, J. Clin. Invest. 1989, 83, 2974-2078; Kost and Langer in xe2x80x9cTopical Drug Bioavailability, Bioequivalence, and Penetrationxe2x80x9d; pp. 91-103, Shah V. P., Maibach H. I., Eds. (Plenum: New York, 1993); Frideman, R. M., xe2x80x9cInterferons: A Primerxe2x80x9d, Academic Press, New York, 1981). For example, U.S. Pat. No. 4,309,989 to Fahim and U.S. Pat. No. 4,767,402 issued to Kost et al. both describe the use of ultrasound in conjunction with transdermal drug delivery. U.S. Pat. No. 4,309,989 discloses the topical application of a medication using ultrasound with a coupling agent such as oil. Ultrasound at a frequency of at least 1000 kHz and a power of one to three W/cm2 was used to cause selective localized intracellular concentration of a zinc containing compound for the treatment of herpes simplex virus.
U.S. Pat. No. 4,309,989, the disclosure of which is specifically incorporated by reference, discloses the use of ultrasound for enhancing and controlling transdermal permeation of a molecule, including drugs, antigens, vitamins, inorganic and organic compounds, and various combinations of these substances, through the skin and into the circulatory system. Ultrasound having a frequency between about 20 kHz. and 10 MHz. and having an intensity between about 0 and 3 W/cm2 is used essentially to drive molecules through the skin and into the circulatory system. A significant drawback to this system is that the resultant enhanced permeability only occurs while the ultrasound is being applied to the skin. Thus, the skin is often damaged due to over exposure to the ultrasound.
Although a variety of ultrasound conditions have been used for sonophoresis, the most commonly used conditions correspond to therapeutic ultrasound (frequency in the range of between one MHz and three MHz, and intensity in the range of between above zero and two W/cm2) (such as that described in the Kost et al. patent). It is a common observation that the typical enhancement induced by therapeutic ultrasound is less than ten-fold. In many cases, no enhancement of transdermal drug transport has been observed upon ultrasound application. Accordingly, a better selection of ultrasound techniques is needed to induce a higher enhancement of transdermal drug transport by sonophoresis.
Application of low-frequency (between approximately 20 and 200 kHz) ultrasound can dramatically enhance transdermal transport of drugs, as described in PCT/US96/12244 by Massachusetts Institute of Technology. Transdermal transport enhancement induced by low-frequency ultrasound was found to be as much as 1000-fold higher than that induced by therapeutic ultrasound. Another advantage of low-frequency sonophoresis as compared to therapeutic ultrasound is that the former can induce transdermal transport of drugs which do not passively permeate across the skin.
In addition to there being a need to deliver drugs through the skin, there is a major medical need to extract analytes through the skin. For example, it is desirable for diabetics to measure blood glucose several times per day in order to optimize insulin treatment and thereby reduce the severe long-term complications of the disease. Currently, diabetics do this by pricking the highly vascularized fingertips with a lancet to perforate the skin, then milking the skin with manual pressure to produce a drop of blood, which is then assayed for glucose using a disposable diagnostic strip and a meter into which this strip fits. This method of glucose measurement has the major disadvantage that it is painful, so diabetics do not like to obtain a glucose measurement as often as is medically indicated.
Therefore, many groups are working on non-invasive and less invasive means to measure glucose, such as micro lancets that are very small in diameter, very sharp, and penetrate only to the interstitium (not to the blood vessels of the dermis). A small sample, from about 0.1 to two xcexcl, of interstitial fluid is obtained through capillary forces for glucose measurements. Other groups have used a laser to breach the integrity of the stratum corneum and thereby make it possible for blood or interstitial fluid to diffuse out of such a hole or to be obtained through such a hole using pneumatic force (suction) or other techniques. An example of such a laser based sampling device is disclosed in U.S. Pat. No. 5,165,418 to Tankovich and WPI ACC No: 94-167045/20 by Budnik (assigned to Venisect, Inc.).
A problem with methods that penetrate the skin to obtain interstitial fluid is that interstitial fluid occurs in the body in a gel like form with little free fluid and in fact is even negative pressure that limits the amount of free interstitial fluid that can be obtained. When a very small hole is made in the skin, penetrating to a depth such that interstitial fluid is available, it takes a great deal of mechanical force (milking, vacuum, or other force) to obtain the quantity of blood used in a glucose meter.
Thus, there has been described methods for application of ultrasound and extraction of analyte that rely on techniques known in the art such as are disclosed in U.S. patent application Ser. No. 08/885,931 filed Jun. 30, 1997, the disclosure of which is hereby incorporated by reference. The methods described therein channel or focus an ultrasound beam onto a small area of skin. In some embodiments, methods and devices utilizing a chamber and ultrasound probe disclosed can be used to non-invasively extract analyte and deliver drugs (i.e., broadly transdermally transport substances). This provides many advantages, including the ability to create a small puncture or localized erosion of the skin tissue, without a large degree of concomitant pain. The number of pain receptors within the ultrasound application site decreases as the application area decreases. Thus, the application of ultrasound to a very small area will produce less sensation and allow ultrasound and/or its local effects to be administered at higher intensities with little pain or discomfort. Channeling of ultrasound geometrically is one way to apply ultrasound to a small area. The oscillation of a small element near or in contact with the surface of the skin is another way to apply ultrasound to a small area. Large forces can be produced locally, resulting in cavitation, mechanical oscillations in the skin itself, and large localized shearing forces near the surface of the skin. The element can also produce acoustic streaming, which refers to the large convective flows produced by ultrasound. This appears to aid in obtaining a sample of blood or interstitial fluid without having to xe2x80x9cmilkxe2x80x9d the puncture site. Ultrasound transducers are known to rapidly heat under continuous operation, reaching temperatures that can cause skin damage. Heat damage to the skin can be minimized by using a transducer that is located away from the skin to oscillate a small element near the skin. In the case of analyte extraction, compounds present on the surface of and/or in the skin can contaminate the extracted sample. The level of contamination increases as skin surface area increases. Surface contamination can be minimized by minimizing the surface area of ultrasound application. Thus, skin permeability can be increased locally, and transiently through the use of the methods and devices described herein, for either drug delivery or measurement of analyte.
Moreover, it has been disclosed that the application of ultrasound is only required once for multiple deliveries or extractions over an extended period of time rather than prior to each extraction or delivery. That is, it has been shown that if ultrasound having a particular frequency and a particular intensity of is applied, multiple analyte extractions or drug deliveries may be performed over an extended period of time. For example, if ultrasound having a frequency of 20 kHz. and an intensity of 10 W/cm2 is applied, the skin retains an increased permeability for a period of up to four hours. This is described more particularly in U.S. Provisional Patent Application No. 60/070,813 filed on Jan. 8, 1998, the disclosure of which is specifically incorporated by reference herein.
Nevertheless, the amount (e.g., duration, intensity, duty cycle etc.) of ultrasound necessary to achieve this permeability enhancement varies widely. Several factors on the nature of skin must be considered. For example, the type of skin which the substance is to pass through varies from species to species, varies according to age, with the skin of an infant having a greater permeability than that of an older adult, varies according to local composition, thickness and density, varies as a function of injury or exposure to agents such as organic solvents or surfactants, and varies as a function of some diseases such as psoriasis or abrasion.
When cavitation is relied upon to enhance transdermal transport, care must be taken to avoid excessive cavitation which can do damage to the skin through the localized increases of heat and pressure characteristic with cavitation phenomena. If the cavitation produced is sporadic or nonuniform, it very difficult to prevent the localized heat and pressure increases.
Therefore, a need has arisen for a method and apparatus that provides homogenous cavitation for use in a transdermal transport system.
According to one embodiment, the present invention comprises an improved ultrasound source. The ultrasound source comprises an ultrasound transmitting element having an axis and a first cross-section along said axis. The ultrasound transmitting element also has a first axial end operable to produce ultrasonic waves and a second axial end. The first axial end comprises a matrix of ultrasound producing portions.
According to another embodiment, the present invention comprises an ultrasound source. The ultrasound souce comprises an ultrasound transmitting element having an axis and a cross-section along the axis. The ultrasound transmitting element also has a first axial end and a second axial end operable to produce ultrasonic waves. The cross-section has an area having a maximum value at the first axial end and a minimum value at the second axial end.
According to another embodiment, the present invention comprises a method for producing homogenous cavitation at an area of skin. The method comprises creating a volume of fluid having a uniformly dispersed concentration of cavitation nuclei adjacent the area of skin. Ultrasound is then applied to the volume of fluid and causes cavitation at the cavitation nuclei.
According to another embodiment, the present invention comprises a method for producing homogenous cavitation at an area of skin. The method comprises creating a volume of fluid having a uniformly dispersed concentration of a first substance adjacent the area of skin. The first substance is a substance that facilitates the production of cavitation. Ultrasound is then applied to the volume of fluid to cause cavitation.
According to another embodiment, the present invention comprises a method for producing homogenous cavitation at an area of skin. An ultrasound source is provided to apply an ultrasonic wave to the area of skin. A screen having a number of opening therein is positioned between the area of skin and the ultrasound source. Finally, ultrasound is applied to the area of skin through the screen. The openings in the screen nucleate cavitation and control the size of cavitation bubbles produced.
According to another embodiment, the present invention comprises an ultrasound device. The ultrasound device includes an ultrasound horn and a housing for the ultrasound horn. The housing has a portion with a reduced inside diameter relative to a diameter of the horn. The reduced inside diameter focuses ultrasonic energy on a small area of skin.